Computational approaches in antibody-drug conjugate optimization for targeted cancer therapy

WOS: 000444683500007PubMed ID: 30068276Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second-and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme [IF/00578/2014]; European Social Fund; Programa Operacional Potencial Humano; Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]; European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000008]; European Regional Development Fund (ERDF), COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation; Portuguese national funds via FCT [POCI-01-0145-FEDER-007440]; FCT [FCT-SFRH/BPD/97650/2013]; Fundacao para a Ciencia e Tecnologia (FCT), Portugal [UID/Multi/04349/2013]Irina S. Moreira acknowledges support by the Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme - IF/00578/2014 (co-financed by European Social Fund and Programa Operacional Potencial Humano), and a Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]. This work was also financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008: Brain-Health 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-007440. Rita Melo acknowledges support from the FCT (FCT-SFRH/BPD/97650/2013). This work has been partially supported by the Fundacao para a Ciencia e Tecnologia (FCT), Portugal, through the UID/Multi/04349/2013 project in Centre for Nuclear Sciences and Technologies (C2TN)

Una Revisión de los Instrumentos de Evaluación del Desgaste en la Seguridad Pública

Objetivou-se mapear os instrumentos utilizados na avaliação da síndrome de Burnout em profissionais da segurança pública, indicando os aspectos psicométricos, amostras e variáveis associadas. Foram selecionados 19 estudos nas bases de dados pesquisadas (PsycINFO, PubMED e Google Scholar). Os resultados indicaram a utilização dos instrumentos MBI-GS, MBI-HSS, BM-S, CBI e CESQT, mas apenas um dos instrumentos apresentou evidência de validade nesse contexto. Constatou-se a associação do Burnout com variáveis pessoais, organizacionais e específicas. A comparação dos estudos e dos índices de Burnout foi limitada devido à falta de padronização. A ausência de evidências de validade e de padronização dos resultados acarreta problemas como a falta de suporte empírico das pontuações e dificuldade na comparação dos estudos. Os dados revelam limitações na avaliação dos níveis de Burnout utilizadas no contexto de segurança pública, uma vez que as medidas não apresentam evidências de validade para esse contexto, indicando a necessidade de pesquisas na área.Aimed to map the instruments used in evaluating Burnout syndrome in public security professionals, indicating the psychometric aspects, samples, and associated variables. Nineteen studies were selected from the searched databases (PsycINFO, PubMED and Google Scholar). Results indicated that the instruments MBI-GS, MBI-HSS, BM-S, CBI and CESQT, but only one of the instruments showed evidence of validity in this context. Burnout was associated with personal, organizational, and specific variables. Comparison of studies and Burnout indices was limited due to the lack of standardization. The absence of evidence of validity and standardization of results leads to problems such as the lack of empirical support for the scores and difficulty in comparing studies. The data reveal limitations in the assessment of burnout levels used in the context of public safety, as the measures do not present validity evidence for this context, pointing to the need for research in the area.El objetivo fue mapear los instrumentos utilizados en la evaluación del síndrome de Burnout en profesionales de la seguridad pública, indicando los aspectos psicométricos, muestras y variables asociadas. Se seleccionaron diecinueve estudios de las bases de datos buscadas (PsycINFO, PubMED y Google Scholar). Los resultados indicaron el uso de los instrumentos MBI-GS, MBIHSS, BM-S, CBI y CESQT, pero solo uno de los instrumentos mostró evidencia de validez en este contexto. El Burnout se encuentra asociado con variables personales, organizacionales y específicas. La comparación de estudios e índices fue limitada debido a la falta de estandarización. La ausencia de evidencia de validez y estandarización de resultados conduce a problemas como la falta de soporte empírico para las puntuaciones y la dificultad para comparar estudios. Los datos revelan limitaciones en la evaluación de los niveles de burnout utilizados en el contexto de la seguridad pública, ya que las medidas no presentan evidencia de validez para este contexto, lo que apunta a la necesidad de realizar investigaciones en el área.info:eu-repo/semantics/publishedVersio

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics

A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.info:eu-repo/semantics/publishedVersio

Do Brazilian scientific journals promote the adherence of Chagas disease researchers to internacional ethical principals?

The ethical aspects of the Brazilian publications about human Chagas disease (CD) developed between 1996 and 2010 and the policy adopted by Brazilian medical journals were analyzed. Articles were selected on the SciELO Brazil data basis, and the evaluation of ethical aspects was based on the normative contents about ethics in research involving human experimentation according to the Brazilian resolution of the National Health Council no. 196/1996. The editorial policies of the section "Instructions to authors" were analyzed. In the period of 1996-2012, 58.9% of articles involving human Chagas disease did not refer to the fulfillment of the ethical aspects concerning research with human beings. In 80% of the journals, the requirements and confirmation of the information about ethical aspects in the studies of human CD were not observed. Although a failure in this type of service is still observed, awareness has been raised in federal agencies, educational institutions/research and publishing groups to standardize the procedures and ethical requirements for the Brazilian journals, reinforcing the fulfillment of the ethical parameters, according to the resolution of NHC no. 196/1996